Combination therapies comprising apremilast and tyk2 inhibitors

ABSTRACT

Provided herein are methods of treating diseases and disorder responsive to the inhibition of PDE4 comprising administering apremilast and a Tyk2 inhibitor to a subject. Also provided herein are pharmaceutical compositions comprising apremilast and a Tyk2 inhibitor.

RELATED APPLICATIONS

This application is continuation of U.S. patent application Ser. No.16/398,569, filed Apr. 30, 2019, the entire contents of which areincorporated herein by reference.

BACKGROUND

N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide(apremilast), marketed as Otezla®, is a phosphodiesterase type 4 (PDE4)inhibitor currently approved for treating both moderate to severe plaquepsoriasis and active psoriatic arthritis. PDE4 inhibition by apremilastelevates cyclic adenosine monophosphate (cAMP) levels in immune cells.This in turn down-regulates inflammatory responses by reducing theexpression of pro-inflammatory mediators such as TNF-α, IL-23, IL-17,and other inflammatory cytokines, and increases the production ofanti-inflammatory mediators. Studies have shown that a 75% reduction inplaque psoriasis is achievable in some patients in as little as justover 4 months of treatment.

Tyrosine kinase 2 (Tyk2), an intracellular signaling enzyme, activatessignal transducer and activator of transcription (STAT)—dependent geneexpression and functional responses of IL-12, IL-23, and type I and IIIinterferon receptors. Amongst other conditions, tyrosine kinaseinhibitors (TKIs) have recently gained attention as effective agents fortreating psoriasis and related conditions. The TKI inhibitor BMS-986165,for example, recently showed positive results in phase 2 clinical trialsin subjects with moderate to severe plaque psoriasis. See Kim Papp, M.D., Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition inPsoriasis, The New England Journal of Medicine, Sep. 12, 2018.

SUMMARY

It has now been found that the combination of apremilast and the Tyk2inhibitor6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide(BMS-986165) synergistically reduces pro-inflammatory cytokinesexpressed in a whole blood assay under conditions that stimulate Th17cells. For example, there was over a 2-fold increase in the inhibitionof IL-17F expression using the combination of 0.01 μM BMS-986165 and 1μM apremilast when compared to the use of each drug alone. See e.g.,Table 5 in the Exemplification section. Similar results were seen at 0.1μM concentrations of BMS-986165 with 1 μM apremilast. See e.g., Table 5.The combination of BMS-986165 with 1 μM apremilast also reduced cytokineexpression for IL-17A and IL-22 at values of 2-fold or greater over theuse of each drug alone. See e.g., Table 5.

It was also found that the combination of apremilast and BMS-986165elicit complementary effects against certain pro-inflammatory cytokines.BMS-986165, for example, increased TNF-α and GM-CSF cytokine in wholeblood assay, while apremilast inhibited the production of thesecytokines. See e.g., Table 5 where the % control for 1 μM apremilast was10.7 and the % control for 0.01 μM BMS-986165 was 143.1 against TNF-α.When administered in combination, however, apremilast corrected thedeficiency of BMS-986165 thereby producing a complementary effect of13.5% inhibition against TNF-α. See e.g., Table 5. This trend was alsoestablished at 0.1 μM concentrations of BMS-986165 and against cytokineGM-CSF. See e.g., Table 5. These results illustrate the synergistic andcomplementary pharmacological effects of BMS-986165 and apremilast.

In addition to whole blood assay, the combination of BMS-986165 andapremilast elicit complementary effects against certain pro-inflammatorycytokines in LPS stimulated PBMCs as well. BMS-986165 increased IL-23,IL-12 and TNF-α, while apremilast inhibited the production of thesecytokines. See e.g., Table 6 in the Exemplification section. Theseresults further support the advantage of combining BMS-986165 andapremilast in treatment of Th17 related diseases.

Provided herein, therefore are methods of treating diseases or disordersresponsive to the inhibition of PDE4 in a subject using an effectiveamount of apremilast, or a pharmaceutically acceptable salt thereof, andan effective amount of a Tyk2 inhibitor such as BMS-986165. Suchdiseases and disorders include e.g., inflammatory diseases such aspsoriasis, psoriatic arthritis, and ulcerative colitis.

Also provided herein are pharmaceutical compositions comprising aneffective amount of apremilast, or a pharmaceutically acceptable saltthereof, and an effective amount of a Tyk2 inhibitor such as BMS-986165.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates interleukin-17a (IL-17a) cytokine production (percentof control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) oranti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated wholeblood—TruCulture® tube assay.

FIG. 2 illustrates interleukin-17A (IL-17A) cytokine production byapremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) oranti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated wholeblood—TruCulture® tube assay.

FIG. 3 illustrates interleukin-17F (IL-17F) cytokine production (percentof control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) oranti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated wholeblood—TruCulture® tube assay.

FIG. 4 illustrates interleukin-17F (IL-17F) cytokine production byapremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) oranti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated wholeblood—TruCulture® tube assay.

FIG. 5 illustrates interleukin-22 (IL-22) cytokine production (percentof control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) oranti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated wholeblood—TruCulture® tube assay.

FIG. 6 illustrates interleukin-22 (IL-22) cytokine production byapremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) oranti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated wholeblood—TruCulture® tube assay.

FIG. 7 illustrates tumor necrosis factor alpha (TNF-α) cytokineproduction (percent of control) by apremilast and BMS-986165 inanti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23(Th17) stimulated whole blood—TruCulture® tube assay.

FIG. 8 illustrates tumor necrosis factor alpha (TNF-α) cytokineproduction by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) oranti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated wholeblood—TruCulture® tube assay.

FIG. 9 illustrates granulocyte-macrophage colony-stimulating factor(GM-CSF) cytokine production (percent of control) by apremilast andBMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β,IL-6 and IL-23 (Th17) stimulated whole blood—TruCulture® tube assay.

FIG. 10 illustrates granulocyte-macrophage colony-stimulating factor(GM-CSF) cytokine production by apremilast and BMS-986165 inanti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23(Th17) stimulated whole blood—TruCulture® tube assay.

FIG. 11 illustrates interleukin-23 (IL-23) cytokine production byapremilast in Lipopolysaccharide (LPS) stimulated peripheral bloodmononuclear cells (PBMCs).

FIG. 12 illustrates interleukin-23 (IL-23) cytokine production byapremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.

FIG. 13 illustrates interleukin-12p40 (IL-12p40) cytokine production byapremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.

FIG. 14 illustrates interleukin-12p70 (IL-12p70) cytokine production byapremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.

FIG. 15 illustrates tumor necrosis factor alpha (TNF-α) cytokineproduction by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.

FIG. 16 illustrates interferon gamma (IFN-γ) cytokine production byapremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.

FIG. 17 illustrates monocyte chemoattractant protein-1 (MCP-1) cytokineproduction by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.

DETAILED DESCRIPTION

In a first embodiment, provided herein are methods for treating adisease or disorder responsive to the inhibition of cyclic nucleotidephosphodiesterase isoenzyme IV (PDE4), the method comprisingadministering to a subject an effective amount ofN-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide(apremilast), or a pharmaceutically acceptable salt thereof, and aneffective amount of a Tyk2 inhibitor.

Alternatively, as part of a first embodiment, provided is the use of aneffective amount ofN-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide(apremilast), or a pharmaceutically acceptable salt thereof, and aneffective amount of a Tyk2 inhibitor, in the manufacture of a medicamentfor treating a disease or disorder responsive to the inhibition ofcyclic nucleotide phosphodiesterase isoenzyme IV (PDE4).

In another alternative, as a part of a first embodiment, provided is aneffective amount ofN-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide(apremilast), or a pharmaceutically acceptable salt thereof, and aneffective amount of a Tyk2 inhibitor, for use in treating a disease ordisorder responsive to the inhibition of cyclic nucleotidephosphodiesterase isoenzyme IV (PDE4).

1. Definitions

N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide(apremilast) is disclosed in U.S. Pat. No. 6,962,940, the contents ofwhich are incorporated herein by reference, and refers to the compoundhaving the following chemical structure:

Apremilast has a chiral center designated as (S) in the chemicalstructure and name. As used herein, this designation means thatapremilast is optically enriched as the (S) enantiomer at this positionin an amount of at least 80%, 90%, 95%, 98%, 99%, or 99.9% relative tothe corresponding (R) enantiomer. Thus, when apremilast is referred toherein as being stereomerically or enantiomerically pure at a specifiedamount, it means that the (S) enantiomer is enriched in that amount. Forexample,N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamidethat is at least 95% stereomerically pure means that the compoundcontains greater than or equal to 95% of the (S) enantiomer and 5% orless of the (R) enantiomer.

Unless otherwise indicated, the administrations described herein includeadministering apremilast prior to, concurrently with, or afteradministration of the Tyk2 inhibitor described herein. Thus,simultaneous administration is not necessary for therapeutic purposes.In one aspect, apremilast and a disclosed Tyk2 inhibitor areadministered together. In another aspect, apremilast and a disclosedTyk2 inhibitor are administered at different times on the same day. Inanother aspect, apremilast and a disclosed Tyk2 inhibitor areadministered at different times as separate tablets or capsules. Inanother aspect, apremilast and a disclosed Tyk2 inhibitor areadministered in a fixed dose combination in the same tablet or capsule.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, or inhibiting the progress of a disease or disorderresponsive to the inhibition of PDE4, or one or more symptoms thereof,as described herein.

The term “subject” means an animal, such as a mammal, and such as ahuman. The terms “subject” and “patient” may be used interchangeably.

The term “effective amount” or “therapeutically effective amount” refersto an amount of a compound described herein that will elicit abiological or medical response of a subject e.g., a dosage of between0.001-100 mg/kg body weight/day.

The term “pharmaceutically acceptable carrier” refers to a non-toxiccarrier, adjuvant, or vehicle that does not adversely affect thepharmacological activity of the compound with which it is formulated,and which is also safe for human use. Pharmaceutically acceptablecarriers, adjuvants or vehicles that may be used in the compositions ofthis disclosure include, but are not limited to, ion exchangers,alumina, aluminum stearate, magnesium stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances (e.g., microcrystalline cellulose, hydroxypropylmethylcellulose, lactose monohydrate, sodium lauryl sulfate, andcrosscarmellose sodium), polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The term “pharmaceutically acceptable salts” refer to salts preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic acids and bases and organic acids and bases. Suitablepharmaceutically acceptable base addition salts for the compoundsdescribed herein include, but are not limited to include metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylene diamine, meglumine(N-methylglucamine) and procaine. Suitable non-toxic acids include, butare not limited to, inorganic and organic acids such as acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methane sulfonic, mucic, nitric,pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic,stearic, succinic, sulfanilic, sulfuric, tartaric acid, andp-toluenesulfonic acid.

“Crystalline” refers to a solid form of a compound wherein there existslong-range atomic order in the positions of the atoms. The crystallinenature of a solid can be confirmed, for example, by examination of theX-ray powder diffraction pattern. A “single crystalline form” means thatthe recited compound, i.e.,N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide,is present as a single crystal or a plurality of crystals in which eachcrystal has the same crystal form (e.g., crystalline Form B). When thecrystal form is defined as a specified percentage of one particularsingle crystalline form of the compound, the remainder is made up ofamorphous form and/or crystalline forms other than the one or moreparticular forms that are specified. In one aspect, e.g., a disclosedcrystalline form is at least 80% a single crystalline form, at least 90%a single crystalline form, at least 95% a single crystalline form, or atleast 99% a single crystalline form by weight. Percent by weight of aparticular crystal form is determined by the weight of the particularcrystal form divided by the sum weight of the particular crystal, plusthe weight of the other crystal forms present plus the weight ofamorphous form present multiplied by 100%.

The term “amorphous” refers to a solid that is present in anon-crystalline state or form. Amorphous solids are disorderedarrangements of molecules and therefore possess no distinguishablecrystal lattice or unit cell and consequently have no definable longrange ordering. Solid state ordering of solids may be determined bystandard techniques known in the art, e.g., by X-ray powder diffraction(XRPD) or differential scanning calorimetry (DSC). Amorphous solids canalso be differentiated from crystalline solids e.g., by birefringenceusing polarized light microscopy.

The 2-theta values of the X-ray powder diffraction patterns for thecrystalline forms described herein may vary slightly from one instrumentto another and also depending on variations in sample preparation andbatch to batch variation due to factors such as temperature variation,sample displacement, and the presence or absence of an internalstandard. Therefore, unless otherwise defined, the XRPDpatterns/assignments recited herein are not to be construed as absoluteand can vary ±0.2 degrees. It is well known in the art that thisvariability will account for the above factors without hindering theunequivocal identification of a crystal form.

2. Tyk2 Inhibitors

Tyk2 inhibitors used in the disclosed methods and compositions includecompounds which block the action of tyrosine kinase 2, a non-receptortyrosine-protein kinase encoded by the Tyk2 gene.

In a second embodiment, the disclosed Tyk2 inhibitors include, but arenot limited to, those described in Xingrui He et al., Expert Opinion onTherapeutics Patents 2019, Vol. 29, No. 2, 137-149, the entire contentsof which are incorporated herein by reference.

In a third embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2015/032423, the entire contents of which areincorporated herein by reference. Exemplary compounds having thisformula as part of the third embodiment include, but are not limited to,those having the formula:

or a pharmaceutically acceptable salt thereof. Other Tyk2 inhibitors aspart of the third embodiment include those in WO 2008/139161, and WO2010/055304, the entire contents of each of which are incorporatedherein by reference.

In a fourth embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2013/174895, the entire contents of which areincorporated herein by reference. Exemplary compounds having thisformula as part of the fourth embodiment include, but are not limitedto, those having the formula:

or a pharmaceutically acceptable salt thereof. Other Tyk2 inhibitorsinclude those in WO 2012/062704, the entire contents of which areincorporated herein by reference.

In a fifth embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2012/062704, the entire contents of which areincorporated herein by reference.

In a sixth embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those having the formulae:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2015/091584, the entire contents of which areincorporated herein by reference. Exemplary compounds having thisformula as part of the sixth embodiment include, but are not limited to,those having the formula:

or a pharmaceutically acceptable salt thereof.

In a seventh embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2016/027195, the entire contents of which areincorporated herein by reference. Exemplary compounds having thisformula as part of the seventh embodiment include, but are not limitedto, those having the formula:

or a pharmaceutically acceptable salt thereof.

In an eighth embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in US 2017/0240552, the entire contents of which areincorporated herein by reference. Exemplary compounds having thisformula as part of the eighth embodiment include, but are not limitedto, those having the formula:

or a pharmaceutically acceptable salt thereof.

In a ninth embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2015/016206, the entire contents of which areincorporated herein by reference.

In a tenth embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2013/146963, the entire contents of which areincorporated herein by reference.

In an eleventh embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2016/047678, the entire contents of which areincorporated herein by reference.

In a twelfth embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those described in US 2015/0299139; WO 2015/069310; U.S. Pat. No.9,505,748; WO 2018/0162889; US 2013/0178478; or WO 2015/123453, theentire contents of each of which are incorporated herein by reference.

In a thirteenth embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2015/131080 or WO 2016/138352, the entire contents ofwhich are incorporated herein by reference.

In a fourteenth embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2017/040757, the entire contents of which areincorporated herein by reference.

In a fifteenth embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2015/131080, WO 2016/138352, and WO 2017/040757, theentire contents of which are incorporated herein by reference.

In a sixteenth embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2018/071794, the entire contents of which areincorporated herein by reference.

In a seventeenth embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2018/075937, the entire contents of which areincorporated herein by reference.

In an eighteenth embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in US 2013/0178478, the entire contents of which areincorporated herein by reference.

In a nineteenth embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2015/123453, the entire contents of which areincorporated herein by reference.

In a twentieth embodiment, the disclosed Tyk2 inhibitors may be selectedfrom those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2015/089143, the entire contents of which areincorporated herein by reference.

In a twenty-first embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2015/089143, the entire contents of which areincorporated herein by reference.

In a twenty-second embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2018/067432, the entire contents of which areincorporated herein by reference.

In a twenty-third embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2018/093968, the entire contents of which areincorporated herein by reference.

In a twenty-fourth embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2018/081488, the entire contents of which areincorporated herein by reference.

In a twenty-fifth embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein

R¹ is C₁₋₃alkyl optionally substituted by 0-7 R^(1a);

R^(1a) at each occurrence is independently hydrogen, deuterium, F, Cl,Br, CF₃ or CN;

R² is C₁₋₆alkyl or —(CH₂)_(r)-3-14 membered carbocycle, each groupsubstituted with 0-4 R^(2a);

R^(2a) at each occurrence is independently hydrogen, ═O, halo, OCF₃, CN,NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆alkynyl substituted with 0-3 R^(a), —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a) or a —(CH₂)_(r)-5-7 membered heterocyclecomprising carbon atoms or 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-2 R^(a);

R³ is C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, or a 5-10 membered heterocyclecontaining 1-4 heteroatoms selected from N, O, and S, each groupsubstituted with 0-4 R^(3a);

R^(3a) at each occurrence is independently hydrogen, ═O, halo, OCF₃,CF₃, CHF₂, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substitutedwith 0-3 R^(a), C₁₋₆haloalkyl, —(CH₂)_(r)− 3-14 membered carbocyclesubstituted with 0-3 R^(a) or a —(CH₂)_(r)-5-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-3 R^(a);

or two R^(3a), together with the atoms to which they are attached,combine to form a fused ring wherein said ring is selected from phenyland a 5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, S or O said fused ring further substitutedby R^(a1);

R⁴ and R⁵ are independently hydrogen, C₁₋₄ alkyl substituted with 0-1R^(f), (CH₂)_(r-)phenyl substituted with 0-3 R^(d), or a —(CH₂)-5-7membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p);

R¹¹ at each occurrence is independently hydrogen, C₁₋₄ alkyl substitutedwith 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH)_(r)-phenyl substituted with 0-3 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p) substituted with 0-3 R^(d);

R^(a) and R^(a1) at each occurrence are independently hydrogen, F, Cl,Br, OCF₃, CF₃, CHF₂, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-3 R^(f), C₁₋₆haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CH₂)_(r)-3-14 memberedcarbocycle or —(CH₂)_(r)-5-7 membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substitutedwith 0-3 R^(f);

R^(b) at each occurrence is independently hydrogen, C₁₋₆ alkylsubstituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substitutedwith 0-2 R^(d), or —(CH₂)_(r)-5-7 membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substitutedwith 0-3 R^(f) or (CH₂)_(r)-phenyl substituted with 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkylsubstituted with 0-3 R^(f), (CH₂)_(r)-phenyl substituted with 0-3 R^(f);or

R^(d) at each occurrence is independently hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl, or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) at each occurrence is independently selected from hydrogen, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) independently at each occurrence is hydrogen, halo, CN, NH₂, OH,C₃₋₆cycloalkyl, CF₃, O(C₁₋₆alkyl), or a —(CH₂)_(r)-5-7 memberedheteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p);

p is 0, 1, or 2; and

r is 0, 1, 2, 3, or 4, wherein additional definitions and specificcompounds can be found e.g., in US 2015/0299139, the entire contents ofwhich are incorporated herein by reference.

In a twenty-sixth embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein

R¹ is C₁₋₃alkyl optionally substituted by 0-7 R^(1a)

R^(1a) at each occurrence is independently hydrogen, deuterium, F, Cl,Br, CF₃ or CN;

R² is C₁₋₆ alkyl substituted with 0-4 R^(2a), C₃₋₆ cycloalkylsubstituted with 0-4 R^(2a), C₆₋₁₀ aryl substituted with 0-4 R^(2a), a5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O,and S, substituted with 0-4 R^(2a), NR⁶R⁶ or OR^(b);

R^(2a) at each occurrence is independently hydrogen, ═O, halo, OCF₃, CN,NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R_(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), (CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(C),—(CH₂)_(r)NR^(b)C(O)OR^(C), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(C), —S(O)_(p)R^(C), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ halo alkyl, —(CH₂)_(r)-3-14 membered carbocycle substitutedwith 0-1 R^(a) or a-(CH₂)_(r)-5-7 membered heterocycle comprising carbonatoms or 1-4 heteroatoms selected from N, O, and S(O)_(p) substitutedwith 0-2 R^(a);

or one R^(2a) and another R^(2a), together with the atoms to which theyare attached, combine to form a fused 5-6 membered ring wherein saidfused ring may be substituted with 0-2 R^(a);

R³ is —(CH₂)_(r)-3-14 membered carbocycle substituted 0-5 R^(3a);

R^(3a) at each occurrence is independently hydrogen, ═O, halo, OCF₃, CN,NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R_(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), (CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(C),—(CH₂)_(r)NR^(b)C(O)OR^(C), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(C), —S(O)_(p)R^(C), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ halo alkyl, —(CH₂)_(r)-3-14 membered carbocycle substitutedwith 0-3 R^(a) or a-(CH₂)_(r)-5-10 membered heterocycle comprisingcarbon atoms or 1-4 heteroatoms selected from N, O, and S(O)_(p)substituted with 0-3 R^(a);

or two R^(3a), together with the atoms to which they are attached,combine to form a fused ring wherein said ring is selected from phenyland a 5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, S or O, said fused ring may be furthersubstituted by R^(a);

R⁴ and R⁵ are independently hydrogen, C₁₋₄ alkyl substituted with 0-1R^(f), (CH₂)_(r)-phenyl substituted with 0-3 R^(d), or a —(CH₂)-5-7membered heterocycle comprising 5 carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)p;

R⁶ and R¹¹ at each occurrence are independently hydrogen, C₁₋₄ alkylsubstituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1R^(f), (CH)_(r)-phenyl substituted with 0-3 R^(d), or —(CH₂)_(r)-5-7membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p) substituted with 0-3 R^(d);

R^(a) at each occurrence is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN,NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(C),—(CH₂)_(r)NR^(b)C(O)OR^(C), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR_(b)S(O)_(p)R^(C), —S(O)R^(C), —S(O)₂R^(C), C₁₋₆alkyl substitutedwith 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle, or—(CH₂)_(r)-5-7 15 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)p substituted with 0-3 R^(f);

R^(b) at each occurrence is hydrogen, C₁₋₆ alkyl substituted with 0-3R^(d), C₁₋₆ halo alkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R_(f),or (CH₂)_(r)-phenyl substituted with 0-3 R^(d);

R^(C) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) at each occurrence is independently hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, OR^(e), —(CH₂)_(r)C(O)R^(C), NR^(e)C(O)OR^(C),NR^(e)C(O)OR^(C), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) at each occurrence is independently selected from hydrogen, C₁₋₆alkyl, C₃₋₆ cycloalkyl and (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) independently at each occurrence is hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆alkyl) or a —(CH₂)_(r)-5-7 memberedheteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p);

p is 0, 1, or 2; and

r is 0, 1, 2, 3, or 4.

In a twenty-seventh embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described in WO 2015/069310, the entire contents of which areincorporated herein by reference.

In a twenty-eighth embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formula:

or a pharmaceutically acceptable salt thereof, wherein

Y is N or CR₆;

R¹ is H, C₁₋₃alkyl or C₃₋₆cycloalkyl, each optionally substituted by 0-7R^(1a);

R^(1a) at each occurrence is independently hydrogen, deuterium, F, Cl,Br or CN;

R² is C₁₋₆alkyl, —(CH₂)_(r)-3-14 membered carbocycle substituted with0-1 R^(2a) or a 5-14 membered heterocycle containing 1-4 heteroatomsselected from N, O, and S, each group substituted with 0-4 R^(2a) (forthe sake of clarity, R² is intended to include substituted methyl groupssuch as —C(O)R^(2a));

R^(2a) at each occurrence is independently hydrogen, ═O, halo, OCF₃, CN,NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆alkynyl substituted with 0-3 R^(a), —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a) or a —(CH₂)_(r)-5-7 membered heterocyclecomprising carbon atoms or 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-2 R^(a);

R³ is C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl or a 5-10 membered heterocyclecontaining 1-4 heteroatoms selected from N, O, and S, each groupsubstituted with 0-4 R^(3a);

R^(3a) at each occurrence is independently hydrogen, ═O, halo, OCF₃,CF₃, CHF₂, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substitutedwith 0-3 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-3 R^(a) or a —(CH₂)_(r)-5-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-3 R^(a);

or two R^(3a), together with the atoms to which they are attached,combine to form a fused ring wherein said ring is selected from phenyland a heterocycle comprising carbon atoms and 1-4 heteroatoms selectedfrom N, O, and S(O)_(p), each fused ring substituted with 0-3 R^(a1);

R⁴ and R⁵ are independently hydrogen, C₁₋₄ alkyl substituted with 0-1R^(f), (CH₂)_(r-)phenyl substituted with 0-3 R^(d) or a —(CH₂)-5-7membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p);

R⁶ is hydrogen, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, OC₁₋₄haloalkyl,OC₁₋₄alkyl, CN, NO₂ or OH;

R¹¹ at each occurrence is independently hydrogen, C₁₋₄ alkyl substitutedwith 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p) substituted with 0-3 R^(d);

R^(a) and R^(a1) at each occurrence are independently hydrogen, F, Cl,Br, OCF₃, CF₃, CHF₂, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR″R″,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CH₂)_(r)-3-14 memberedcarbocycle or —(CH₂)_(r)-5-7 membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substitutedwith 0-3 R^(f);

R^(b) is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p) substituted with 0-3 R^(f) or(CH₂)_(r)-phenyl substituted with 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)-C₃₋₆cycloalkylsubstituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(d) at each occurrence is independently hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) at each occurrence is independently selected from hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl and (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) independently at each occurrence is hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p);

p is 0, 1, or 2; and

r is 0, 1, 2, 3, or 4, wherein additional definitions and specificcompounds are as described in U.S. Pat. No. 9,505,748 and WO2018/0162889, the entire contents of each of which are incorporatedherein by reference.

In a twenty-ninth embodiment, the disclosed Tyk2 inhibitors may beselected from those having the formulae:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is

and

R² is

In a thirtieth embodiment, the Tyk2 inhibitor described herein is6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide(BMS-986165), having the following chemical structure:

or a pharmaceutically acceptable salt thereof.

The specific dosage and treatment regimen for a disclosed Tyk2 inhibitorto be used in combination with apremilast will depend upon a variety offactors, including age, body weight, general health, sex, diet, time ofadministration, rate of excretion, drug combination, the judgment of thetreating physician, and the severity of the particular disease beingtreated.

In a thirty-first embodiment, the effective amount of a disclosed Tyk2inhibitor (e.g., as in any one of the second to thirtieth embodiment) tobe used in combination with apremilast ranges from 0.001 to 50 mg/kgbody weight/day. For example, as part of a thirty-first embodiment, theeffective amount of a disclosed Tyk2 inhibitor (e.g., as in any one ofthe second to thirtieth embodiment) to be used in combination withapremilast ranges from about 0.1 mg/day to about 250 mg/day, e.g., fromabout 0.2 mg/day to about 100 mg./day, about 0.5 mg/day to about 50mg/day, and about 1.0 mg to about 24 mg/day.

In a thirty-second embodiment, the Tyk2 inhibitor described herein isBMS-986165, or a pharmaceutically acceptable salt thereof, and theeffective amount of BMS-986165, or a pharmaceutically acceptable saltthereof, ranges from about 0.1 mg/day to about 250 mg/day, about 0.1mg/day to about 100 mg/day, about 0.1 mg/day to about 50 mg/day, about0.1 mg/day to about 25 mg/day 0.1 mg/day to about 15 mg/day, about 0.1mg/day to about 10 mg/day, about 0.5 mg/day to about 15 mg/day, about0.5 mg/day to about 10 mg/day, about 0.1 mg/day to about 5 mg/day, about0.5 mg/day to about 5 mg/day, about 1 mg/day to about 25 mg/day, about 2mg/day to about 14 mg/day, about 2 mg/day to about 12 mg/day, or about 3mg/day to about 12 mg/day. Alternatively, as part of a thirty-secondembodiment, the effective amount of BMS-986165, or a pharmaceuticallyacceptable salt thereof ranges from about 1 mg/day to about 15 mg/day,about 1 mg/day to about 14 mg/day, about 2 mg/day to about 14 mg/day,about 2 mg/day to about 12 mg/day, or about 3 mg/day to about 12 mg/day.

In a thirty-third embodiment, the Tyk2 inhibitor described herein isBMS-986165, or a pharmaceutically acceptable salt thereof, and theeffective amount of BMS-986165, or a pharmaceutically acceptable saltthereof, is about 0.1 mg/day, about 0.5 mg/day, about 1.0 mg/day, about2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day,about 11 mg/day, or about 12 mg/day. Alternatively, as part of athirty-third embodiment, the effective amount of BMS-986165, or apharmaceutically acceptable salt thereof, is about 2 mg/day, about 3mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day,about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, orabout 12 mg/day. In another alternative, as part of a thirty-thirdembodiment, the effective concentration of BMS-986165, or apharmaceutically acceptable salt thereof, is about 1 nM to about 1 μM(e.g., from about 0.01 μM to about 0.1 μM).

3. Apremilast

As described above, apremilast is optically enriched as the (S)enantiomer. In a thirty-fourth embodiment, the stereomeric purity ofapremilast in the methods and compositions described herein is greaterthan 90%, wherein the Tyk2 inhibitor and related features are asdescribed herein e.g., as in any one of the first to thirty-thirdembodiments. Alternatively, as part of a thirty-fourth embodiment, thestereomeric purity of apremilast in the methods and compositionsdescribed herein is greater than 95%, wherein the Tyk2 inhibitor andrelated features are as described herein e.g., as in any one of thefirst to thirty-third embodiments. In another alternative, as part of athirty-fourth embodiment, the stereomeric purity of apremilast in themethods and compositions described herein is greater than 97%, whereinthe Tyk2 inhibitor and related features are as described herein e.g., asin any one of the first to thirty-third embodiments. In anotheralternative, as part of a thirty-fourth embodiment, the stereomericpurity of apremilast in the methods and compositions described herein isgreater than 98%, wherein the Tyk2 inhibitor and related features are asdescribed herein e.g., as in any one of the first to thirty-thirdembodiments. In another alternative, as part of a thirty-fourthembodiment, the stereomeric purity of apremilast in the methods andcompositions described herein is greater than 99%, wherein the Tyk2inhibitor and related features are as described herein e.g., as in anyone of the first to thirty-third embodiments. In another alternative, aspart of a thirty-fourth embodiment, the stereomeric purity of apremilastin the methods and compositions described herein is greater than 99.5%,wherein the Tyk2 inhibitor and related features are as described hereine.g., as in any one of the first to thirty-third embodiments. In anotheralternative, as part of a thirty-fourth embodiment, the stereomericpurity of apremilast in the methods and compositions described herein isgreater than 99.9%, wherein the Tyk2 inhibitor and related features areas described herein e.g., as in any one of the first to thirty-thirdembodiments.

Polymorphic forms of apremilast are included in the disclosed methodsand compositions and include e.g., those described in U.S. Pat. No.9,018,243, the entire contents of which are incorporated herein byreference. In a thirty-fifth embodiment, apremilast in the disclosedmethods and compositions is a single crystalline form, whereinadditional features for apremilast as well as the Tyk2 inhibitor andrelated features are as described herein e.g., as in any one of thefirst to thirty-fourth embodiments.

In a thirty-sixth embodiment, apremilast in the disclosed methods andcompositions is a single crystalline Form B characterized by X-raypowder diffraction peaks at 2Θ angles selected from 10.1°, 13.5°, 20.7°,and 26.9°, wherein additional features for apremilast as well as theTyk2 inhibitor and related features are as described herein e.g., as inany one of the first to thirty-fourth embodiments. Alternatively, aspart of a thirty-sixth embodiment, apremilast in the disclosed methodsand compositions is a single crystalline Form B characterized by X-raypowder diffraction peaks at 2Θ angles selected from 10.1°, 13.5°, 15.7°,18.1°, 20.7°, 24.7°, and 26.9°, wherein additional features forapremilast as well as the Tyk2 inhibitor and related features are asdescribed herein e.g., as in any one of the first to thirty-fourthembodiments. In another alternative, as part of a thirty-sixthembodiment, apremilast in the disclosed methods and compositions is asingle crystalline Form B characterized by X-ray powder diffractionpeaks at 2Θ angles selected from 10.1°, 13.5°, 15.7°, 16.3°, 18.1°,20.7°, 22.5°, 24.7°, 26.2°, 26.9°, and 29.1°, wherein additionalfeatures for apremilast as well as the Tyk2 inhibitor and relatedfeatures are as described herein e.g., as in any one of the first tothirty-fourth embodiments.

In a thirty-seventh embodiment, apremilast in the disclosed methods andcompositions is at least 90% single crystalline Form B, whereinadditional features for apremilast as well as the Tyk2 inhibitor andrelated features are as described herein e.g., as in any one of thefirst to thirty-sixth embodiments. Alternatively, apremilast in thedisclosed methods and compositions is at least 95% single crystallineForm B, wherein additional features for apremilast as well as the Tyk2inhibitor and related features are as described herein e.g., as in anyone of the first to thirty-sixth embodiments. In another alternative,apremilast in the disclosed methods and compositions is at least 99%single crystalline Form B, wherein additional features for apremilast aswell as the Tyk2 inhibitor and related features are as described hereine.g., as in any one of the first to thirty-sixth embodiments.

The specific dosage and treatment regimen of apremilast, or apharmaceutically acceptable salt thereof, to be used in combination witha disclosed Tyk2 inhibitor will depend upon a variety of factors,including age, body weight, general health, sex, diet, time ofadministration, rate of excretion, drug combination, the judgment of thetreating physician, and the severity of the particular disease beingtreated.

For example, in a thirty-eighth embodiment, the effective amount ofapremilast, or the pharmaceutically acceptable salt thereof, ranges fromabout 0.5 mg to about 1000 mg per day, about 1 mg to about 1000 mg perday, about 5 mg to about 500 mg per day, about 10 mg to about 200 mg perday, about 10 mg to about 100 mg per day, about 40 mg to about 100 mgper day, about 20 mg to about 40 mg per day, about 0.1 mg to about 10 mgper day, about 0.5 mg to about 5 mg per day, about 1 mg to about 20 mgper day, and about 1 mg to about 10 mg per day, about 1 mg to about 100mg per day, about 1 mg to about 80 mg per day, about 5 mg to about 70 mgper day, and about 10 mg to about 60 mg per day, wherein additionalfeatures for apremilast as well as the Tyk2 inhibitor and relatedfeatures are as described herein e.g., as in any one of the first tothirty-seventh embodiments. Alternatively, as part of a thirty-eighthembodiment, the effective amount of apremilast, or the pharmaceuticallyacceptable salt thereof, ranges from about 10 mg to about 60 mg per day,wherein additional features for apremilast as well as the Tyk2 inhibitorand related features are as described herein e.g., as in any one of thefirst to thirty-seventh embodiments. In another alternative, as part ofa thirty-eighth embodiment, the effective amount of apremilast, or thepharmaceutically acceptable salt thereof, ranges from about 40 mg toabout 100 mg per day, wherein additional features for apremilast as wellas the Tyk2 inhibitor and related features are as described herein e.g.,as in any one of the first to thirty-seventh embodiments. In anotheralternative, as part of a thirty-eighth embodiment, the effective amountof apremilast, or the pharmaceutically acceptable salt thereof, rangesfrom between about 40 mg to between about 100 mg per day, whereinadditional features for apremilast as well as the Tyk2 inhibitor andrelated features are as described herein e.g., as in any one of thefirst to thirty-seventh embodiments. In another alternative, as part ofa thirty-eighth embodiment, the effective amount of apremilast, or thepharmaceutically acceptable salt thereof, ranges from about 4 mg toabout 10 mg per day, wherein additional features for apremilast as wellas the Tyk2 inhibitor and related features are as described herein e.g.,as in any one of the first to thirty-seventh embodiments. In anotheralternative, as part of a thirty-eighth embodiment, the effective amountof apremilast, or the pharmaceutically acceptable salt thereof, rangesfrom between about 4 mg to between about 10 mg per day, whereinadditional features for apremilast as well as the Tyk2 inhibitor andrelated features are as described herein e.g., as in any one of thefirst to thirty-seventh embodiments. In another alternative, as part ofa thirty-eighth embodiment, the effective amount of apremilast, or thepharmaceutically acceptable salt thereof, is about 1 mg per day, about 2mg per day, about 3 mg per day, about 4 mg per day, about 5 mg per day,about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25mg per day, about 30 mg per day, about 35 mg per day, about 40 mg perday, about 45 mg per day, about 50 mg per day, about 55 mg per day, orabout 60 mg per day, wherein additional features for apremilast as wellas the Tyk2 inhibitor and related features are as described herein e.g.,as in any one of the first to thirty-seventh embodiments. In anotheralternative, as part of a thirty-eighth embodiment, the effective amountof apremilast, or the pharmaceutically acceptable salt thereof, is about30 mg per day or about 60 mg per day, wherein additional features forapremilast as well as the Tyk2 inhibitor and related features are asdescribed herein e.g., as in any one of the first to thirty-seventhembodiments. In another alternative, as part of a thirty-eighthembodiment, apremilast is administered at a dose of about 30 mg oncedaily, wherein additional features for apremilast as well as the Tyk2inhibitor and related features are as described herein e.g., as in anyone of the first to thirty-seventh embodiments. In another alternative,as part of a thirty-eighth embodiment, apremilast is administered at adose of about 30 mg twice daily, wherein additional features forapremilast as well as the Tyk2 inhibitor and related features are asdescribed herein e.g., as in any one of the first to thirty-seventhembodiments. In another alternative, as part of a thirty-eighthembodiment, the effective concentration of apremilast is about 100 nM toabout 10 μM (e.g., from about 0.1 μM to about 1 μM), wherein additionalfeatures for apremilast as well as the Tyk2 inhibitor and relatedfeatures are as described herein e.g., as in any one of the first tothirty-seventh embodiments.

In a thirty-ninth embodiment, apremilast is titrated to a dosage ofabout 30 mg administered twice daily using the following titrationschedule:

Day 1: about 10 mg in morning;

Day 2: about 10 mg in morning and about 10 mg in evening;

Day 3: about 10 mg in morning and about 20 mg in evening;

Day 4: about 20 mg in morning and about 20 mg in evening;

Day 5: about 20 mg in morning and about 30 mg in evening; and

Day 6 and thereafter: about 30 mg twice daily, wherein additionalfeatures for apremilast as well as the Tyk2 inhibitor and relatedfeatures are as described herein e.g., as in any one of the first tothirty-seventh embodiments. Alternatively, apremilast is titrated to adosage of between about 40 mg/day to between about 100 mg/day using thefollowing titration schedule:

Day 1: about 10 mg in morning;

Day 2: about 10 mg in morning and about 10 mg in evening;

Day 3: about 10 mg in morning and about 20 mg in evening;

Day 4: about 20 mg in morning and about 20 mg in evening;

Day 5: about 20 mg in morning and about 30 mg in evening; and

Day 6 and thereafter: between about 40 mg/day to between about 100mg/day, wherein additional features for apremilast as well as the Tyk2inhibitor and related features are as described herein e.g., as in anyone of the first to thirty-seventh embodiments. In another alternative,apremilast is titrated to a dosage of about 20 mg administered twicedaily using the following titration schedule:

Day 1: about 10 mg in morning;

Day 2: about 10 mg in morning and about 10 mg in evening;

Day 3: about 10 mg in morning and about 20 mg in evening;

Day 4: about 20 mg in morning and about 20 mg in evening;

Day 5: about 20 mg in morning and about 30 mg in evening; and

Day 6 and thereafter: about 20 mg twice daily, wherein additionalfeatures for apremilast as well as the Tyk2 inhibitor and relatedfeatures are as described herein e.g., as in any one of the first tothirty-seventh embodiments. In yet another alternative, apremilast istitrated to a dosage of between about 4 mg/day to between about 10mg/day using the following titration schedule:

Day 1: about 1 mg in morning;

Day 2: about 1 mg in morning and about 1 mg in evening;

Day 3: about 1 mg in morning and about 2 mg in evening;

Day 4: about 2 mg in morning and about 2 mg in evening;

Day 5: about 2 mg in morning and about 3 mg in evening; and

Day 6 and thereafter: between about 4 mg/day to between about 10 mg/day,wherein additional features for apremilast as well as the Tyk2 inhibitorand related features are as described herein e.g., as in any one of thefirst to thirty-seventh embodiments. In yet another alternative,apremilast is titrated to a dosage of about 3 mg administered twicedaily using the following titration schedule:

Day 1: about 1 mg in morning;

Day 2: about 1 mg in morning and about 1 mg in evening;

Day 3: about 10 mg in morning and about 2 mg in evening;

Day 4: about 2 mg in morning and about 2 mg in evening;

Day 5: about 2 mg in morning and about 3 mg in evening; and

Day 6 and thereafter: about 3 mg twice daily, wherein additionalfeatures for apremilast as well as the Tyk2 inhibitor and relatedfeatures are as described herein e.g., as in any one of the first tothirty-seventh embodiments.

3. Compositions and Administration

Also provided herein are pharmaceutical compositions comprising atherapeutically effective amount of apremilast, or a pharmaceuticallyacceptable salt thereof; and a therapeutically effective amount of aTyk2 inhibitor (e.g., BMS-986165). Features for the disclosedpharmaceutical compositions include elements described above e.g., as inany one of the first to thirty-eighth embodiments.

Further provided are pharmaceutical compositions comprising atherapeutically effective amount of apremilast, or a pharmaceuticallyacceptable thereof; and a therapeutically effective amount of a Tyk2inhibitor (e.g., BMS-986165), for use in treating a disease or disorderresponsive to the inhibition of PDE4. Features for the disclosedpharmaceutical compositions include elements described above e.g., as inany one of the first to thirty-eighth embodiments.

Pharmaceutical compositions and single unit dosage forms comprisingapremilast and a Tyk2 inhibitor (e.g., BMS-986165) alone or together ina fixed dose for administration as described above (e.g., as in any oneof the first to thirty-eighth embodiments) is included. Single unitdosage forms of the disclosed methods and compositions are suitable fororal, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal),parenteral (e.g., Subcutaneous, intravenous, bolus injection,intramuscular, or intraarterial), or transdermal administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; ointments;cataplasms (poultices); pastes; powders; dressings; creams; plasters;solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels;liquid dosage forms suitable for oral or mucosal administration to apatient, including suspensions (e.g., aqueous or non-aqueous liquidsuspensions, oil-in-water emulsions, or a water-in-oil liquidemulsions), solutions, and elixirs; liquid dosage forms suit able forparenteral administration to a patient; and sterile solids (e.g.,crystalline or amorphous solids) that can be reconstituted to provideliquid dosage forms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms of the will typicallyvary depending on their use. For example, a dosage form used in theacute treatment of inflammation or a related disorder may contain largeramounts of one or more of the active ingredients it comprises than adosage form used in the chronic treatment of the same disease.Similarly, a parenteral dosage form may contain smaller amounts of oneor more of the active ingredients it comprises than an oral dosage formused to treat the same disease or disorder. These and other ways inwhich specific dosage forms encompassed by this invention will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,Easton Pa. (1990).

In a thirty-ninth embodiment, apremilast in the disclosed methods andcompositions is administered parenterally, transdermally, mucosally,nasally, buccally, sublingually, or orally, wherein additional featuresfor apremilast as well as the Tyk2 inhibitor and related features are asdescribed herein e.g., as in any one of the first to thirty-eighthembodiments. Alternatively, as part of a thirty-ninth embodiment,apremilast in the disclosed methods and compositions is administeredorally, wherein additional features for apremilast as well as the Tyk2inhibitor and related features are as described herein e.g., as in anyone of the first to thirty-eighth embodiments.

In a fortieth embodiment, apremilast in the disclosed methods andcompositions is administered orally in the form of a tablet or acapsule, wherein additional features for apremilast as well as the Tyk2inhibitor and related features are as described herein e.g., as in anyone of the first to thirty-ninth embodiments.

In a forty-first embodiment, apremilast in the disclosed methods andcompositions is formulated as an extended release form, whereinadditional features for apremilast as well as the Tyk2 inhibitor andrelated features are as described herein e.g., as in any one of thefirst to thirty-ninth embodiments.

In a forty-second embodiment, apremilast in the disclosed methods andcompositions is formulated as an immediate release form, whereinadditional features for apremilast as well as the Tyk2 inhibitor andrelated features are as described herein e.g., as in any one of thefirst to thirty-ninth embodiments.

In a forty-third embodiment, both the apremilast and the Tyk2 inhibitorin the disclosed methods and compositions are administered in fixeddosage combination as a once a day formulation, wherein additionalfeatures for apremilast as well as the Tyk2 inhibitor and relatedfeatures are as described herein e.g., as in any one of the first toforty-second embodiments.

4. Conditions Treated by the Methods and Compositions Disclosed Herein

Diseases or disorders that are responsive to the inhibition of PDE4using the methods and compositions disclosed herein include e.g., viral,genetic, inflammatory, allergic, and autoimmune conditions.

In one aspect, the disease or disorder responsive to the inhibition ofPDE4 is selected from chronic obstructive pulmonary disease, asthma,chronic pulmonary inflammatory disease, hyperoxic alveolar injury,inflammatory skin disease, psoriasis, psoriatic arthritis, rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, atopic dermatitis,rheumatoid spondylitis, depression, osteoarthritis, contact dermatitis,ankylosing spondylitis, lupus, lupus nephritis, cutaneous lupuserythematosus, systemic lupus erythrematosus, erythema nodosum leprosum,Sjögren's syndrome, inflammatory bowel disease, Crohn's Disease,Behçet's Disease, and ulcerative colitis.

In one aspect, the disease or disorder responsive to the inhibition ofPDE4 is selected from psoriasis, psoriatic arthritis, contactdermatitis, systemic lupus erythrematosus, cutaneous lupuserythematosus, and ulcerative colitis.

In one aspect, the disease or disorder responsive to the inhibition ofPDE4 is psoriasis. In another aspect, the disease or disorder responsiveto the inhibition of PDE4 is psoriasis and the subject being treated isa candidate for phototherapy or systematic therapy.

In one aspect, the disease or disorder responsive to the inhibition ofPDE4 is plaque psoriasis. In another aspect, the disease or disorderresponsive to the inhibition of PDE4 is plaque psoriasis and the subjectbeing treated is a candidate for phototherapy or systematic therapy.

In one aspect, the disease or disorder responsive to the inhibition ofPDE4 is moderate to severe plaque psoriasis. In another aspect, thedisease or disorder responsive to the inhibition of PDE4 is severeplaque psoriasis and the subject being treated is a candidate forphototherapy or systematic therapy.

In one aspect, the disease or disorder responsive to the inhibition ofPDE4 is psoriatic arthritis.

In one aspect, the disease or disorder responsive to the inhibition ofPDE4 is active psoriatic arthritis.

In one aspect, the disease or disorder responsive to the inhibition ofPDE4 is heart disease, such as congestive heart failure, cardiomyopathy,pulmonary edema, endotoxin-mediated septic shock, acute viralmyocarditis, cardiac allograft rejection, and myocardial infarction.

In one aspect, the disease or disorder responsive to the inhibition ofPDE4 is HIV, hepatitis, adult respiratory distress syndrome,bone-resorption diseases, cystic fibrosis, septic shock, sepsis,endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemicreperfusion injury, meningitis, fibrotic disease, cachexia, graftrejection, osteoporosis, multiple sclerosis, and radiation damage.

In one aspect, the disease or disorder responsive to the inhibition ofPDE4 is cancer of the head, thyroid, neck, eye, skin, mouth, throat,esophagus, cheat, bone, blood, bone marrow, lung, colon, sigmoid,rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas,brain, intestine, heart, adrenal, subcutaneous tissue, lymph nodes,heart, and combinations thereof.

In one aspect, the disease or disorder responsive to the inhibition ofPDE4 is multiple myeloma, malignant melanoma, malignant glioma, acutelymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acutelymphoblastic T-cell leukemia, acute myeloblastic leukemia, acutepromyelocytic leukemia, acute monoblastic leukemia, acuteerythroleukemic leukemia, acute megakaryoblastic leukemia, acutemyelomonocytic leukemia, acute nonlymphocyctic leukemia, acuteundifferentiated leukemia, chronic myelocytic leukemia, chroniclymphocytic leukemia, hairy cell leukemia, multiple myeloma and acute,lymphoblastic leukemia, myelogenous leukemia, lymphocytic leukemia, andmyelocytic leukemia.

In one aspect, the disease or disorder responsive to the inhibition ofPDE4 is a solid tumor, such as sarcoma, fibrosarcoma, myxosarcoma,liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,syn-ovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer,ovarian cancer, prostate cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary car-cinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarci-noma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma,hemangioblas-toma, acoustic neuroma, oligodendroglioma, menangioma,melanoma, neuroblastoma, and retinoblastoma.

EXEMPLIFICATION 1. Materials

TABLE 1 Whole blood assay: Study Materials and Reagents. Name ofMaterial Vendor Catalog#/Lot# Null TruCulture ® Tube Myriad RBM782-001086/11437EO CD3/CD28 TruCulture ® Tube Myriad RBM782-001125/11761EQ IL-1β, IL-6 and IL-23 R&D Systems 201-LB/206-IL/recombinant proteins 1290-IL Magpix Kit with Th17 Cytokines MilliporeHT17MG-14K-PX25 Abcam Simplestep IL-22 Abcam ab216170 ELISA kit

TABLE 2 LPS stimulated PBMCs assay: Study Materials and Reagents Name ofMaterial Vendor Catalog# SepMate ® PBMC Isolation Tube Stemcell 85450Ficoll-Paque PLUS GE Healthcare 17-1440-03 RPM1 Medium 1640 Gibco 11875Fetal bovine serum (FBS) Gibco 10082-147 PBS Gibco 10010-023 40 μm cellstrainer Falcon 352340 RBC lysis buffer eBioscience 00-4333-57 96 wellplates Corning Costar 3610 96 well plates for supernatants CorningCostar 3363 Lipopolysaccharides (LPS) Sigma L4391 Bio-Plex Pro ™ HumanTh17 Bio-Rad 171BA009M Cytokine IL-23 Set Bio-Plex Pro ™ HumanInflammation Bio-Rad 171BL015M Panel 1 IL-12 (p40) Set Bio-Plex Pro ™Human Cytokine Bio-Rad M500KCAF0Y 27-plex Assay

TABLE 3 Test Articles for Studies Compound Lot# Company Apremilast61983-04 Celgene PDE4i Corporation BMS-986165 Available from Medkoo(555349) Celgene or MedChemExpress (HY- Corporation 117287)

2. General Methods

Whole blood was received through the Celgene Donor program afterinformed consent and donor deidentification. All volunteers were healthyand were not on any medications for at least 72 hours prior to the blooddraw. Blood was collected in sodium heparin tubes. The assay was startedwithin 2 hours of the blood draw.

An ex-vivo stimulation of healthy donor human whole blood was performedunder two different stimulation conditions. Condition Th0 was astimulation with TruCulture® tubes containing anti-CD3/anti-CD28.Condition Th17 was a stimulation with TruCulture® tubes containinganti-CD3/anti-CD28 plus IL-1β, IL-6 and IL-23. Whole blood was separatedinto 15 milliliter conical tubes and pre-treated with DMSO, apremilastalone, BMS-986165 alone or BMS-986165 combined with apremilast. Finalconcentrations were 0.2% DMSO, 1 μM for apremilast alone, 1 μM, 0.1 μM,0.01 μM and 0.001 μM BMS-986165 alone and in combination with 1 μMapremilast. Blood was mixed well and then incubated in a 37° C./5% CO₂incubator for 1 hour.

The anti-CD3/anti-CD28 (200 ng/ml and 330 ng/ml final concentrationsrespectively) TruCulture® tubes were thawed on the bench top for 30minutes and then labeled. Plungers were pressed and then broken off.TruCulture® tubes were placed in a rack standing upright such that theplunger side is pointing down in the rack and the tube-cap is pointingup. While blood was incubating with compound Human recombinant IL-6,IL-1β and IL-23 were added to all Th17 tubes in the followingconcentrations: 120 ng IL-6, 120 ng IL-1b and 150 ng IL-23. One ml ofthe pre-treated whole blood was placed in each tube, using sterilepyrogen-free pipette tips. The cap was replaced and the contents of thetube were mixed by inverting 3 times. The tubes were immediately placedin a 37° C. heat block and incubated for 42 hours (tube-cap end). Afterthe 42 hours the tubes were removed from the heat block, tops wereunscrewed and 250 μl of the supernatant was removed and transferred intothree 96-well polypropylene plates. Samples were immediately frozen at−80° C. The supernatants were then thawed at room temperature and testedneat for cytokine production by Luminex Multi-Plex MagPix technology(Millipore) or IL-22 by ELISA (Abcam). The manufacturer's procedureswere followed accordingly.

Peripheral blood mononuclear cells (PBMCs) isolation: Whole blood wasreceived through the Celgene Donor program after informed consent anddonor deidentification. All volunteers were healthy and were not on anymedications for at least 72 hours prior to the blood draw. Blood wascollected in Sodium Heparin tubes and were used within 2 hours of theblood draw for PBMCs isolation. Before PBMCs isolation, whole blood wasdiluted 1:1 with PBS solution containing 2% FBS (2% FBS-PBS). 13 ml ofFicoll-Paque solution was loaded in the SepMate® tube and 25 ml ofdiluted blood was loaded on top of the Ficoll-Paque. Centrifugation at1200 g for 15 minutes with the brake on for cell separation, after whichisolated PBMCs were transferred into a new tube. PBMCs were washed with2% FBS-PBS and centrifuged at 800 g 10 minutes. Pellets were resuspendedin 2% FBS-PBS and filtered through a 40 μm cell strainer to obtainsingle-cell suspension. 3 ml of RBC lysis buffer were used to eliminatered blood cells in the isolated population. Isolated PBMCs were washedwith 2% FBS-PBS and were resuspended in RPMI growth medium containing10% FBS and antibiotics.

For Example 6-11, PBMCs from 9 healthy donors were isolated andLPS-stimulated ex-vivo for IL-23, IL-12p40, IL-12p70, TNF-α, IFN-γ andMCP-1 cytokine analysis. PBMCs were plated in 96 well plate at a densityof 200,000 cells per well in 200 μl of RPMI growth medium containing 10%FBS followed by treatment with DMSO and compounds. Each well receivedthe same amount of DMSO, which is 0.3% v/v as final concentration.Series dilutions of compound treatment was performed according to Table4 shown below. After two hours of compound treatment, LPS 100 ng/ml asfinal concentration was used as the stimulator. PBMCs were thenincubated in a 37° C./5% CO₂ incubator for 16 hours.

TABLE 4 Compound treatment conditions for PBMC assays TreatmentStimulation DMSO No DMSO LPS 100 ng/ml Single compound: LPS 100 ng/mlTyk2i (BMS-986165): 2 μM max, 8 point, 3 fold dilution series (Finalconcentration were 2 μM, 0.66 μM, 0.22 μM, 0.07 μM, 0.02 μM, 0.008 μM,0.002 μM, 0.0009 μM) Single compound: LPS 100 ng/ml Apremilast(CC-10004): 3 μM max, 8 point, 3 fold dilution series (Finalconcentration were 3 μM, 1 μM, 0.33 μM, 0.11 μM, 0.037 μM, 0.012 μM,0.004 μM, 0.001 μM) Combination of Tyk2i and Apremilast: LPS 100 ng/mlTyk2i (BMS-986165): 2 μM max, 8 point, 3 fold dilution series ApremilastCC-10004: fixed concentration at 1 μM Combination of Tyk2i andApremilast: LPS 100 ng/ml Tyk2i (BMS-986165): 2 μM max, 8 point, 3 folddilution series Apremilast CC-10004: fixed concentration at 0.3 μMCombination of Tyk2i and Apremilast: LPS 100 ng/ml Tyk2i (BMS-986165): 2μM max, 8 point, 3 fold dilution series Apremilast CC-10004: fixedconcentration at 0.1 μM Combination of Tyk2i and Apremilast: LPS 100ng/ml Tyk2i (BMS-986165): 2 μM max, 8 point, 3 fold dilution seriesApremilast CC-10004: fixed concentration at 0.037 μM

After 16 hours incubation, supernatants were collected into new 96-wellpolypropylene plates and centrifuged at 4000 rpm for 10 minutes to getrid of cell debris. Cytokine production was measured by Luminex Bio-PlexMultiplex Immunoassay (Bio-Rad) according to the manufacturer'sprocedures. To ensure that supernatant level was within the range of thestandard cytokine for the assay, samples were diluted 5 fold forIL-12p40 and 27-plex assays, and used neat for IL-23 assay.

3. Data Analysis

Data processing for the cytokine analysis was done using MilliplexAnalyst (Millipore), and raw data was exported to Excel template for thecytokine analysis. Data from the template was plotted using GraphPadPrism 7.0 (GraphPad Software, Inc., La Jolla, Calif.) and expressed aspg/ml or % of control. Statistical analysis was also performed using OneWay Anova and Dunnett's Post Test.

Data processing for PBMCs assays was done using Bio-plex manager, andraw data was exported to Excel template for the cytokine analysis. Datawas plotted using GraphPad Prism 7.0 (GraphPad Software, Inc., La Jolla,Calif.) and expressed as % of DMSO control. Statistical analysis wasperformed using One Way ANOVA and Tukey's multiple comparisons test.

To evaluate the combinatory effect of apremilast and BMS-986165, datafrom the two independent treatments were analyzed by comparing thecombinatory response against the theoretical additive response of thetwo agents. The expected additive effect of two agents (A and B) wascalculated using the fractional product method: (fu)A,B=(fu)A×(fu)B;where fu=fraction unaffected by treatment. A synergism of a combinationis determined when the observed fraction unaffected in combination isless than (fu)A,B, whereas an additive effect is determined when theobserved fraction unaffected in combination equals (fu)A,B. A partiallyadditive effect is indicated when the observed fraction unaffected incombination is greater than (fu)A,B.

Example 1 Interleukin 17A Cytokine Production by Apremilast andBMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β,IL-6 and IL-23 (Th17) Stimulated Whole Blood

Whole blood from 4 healthy donors were analyzed for IL-17A, IL-17F,IL-22, TNF-α and GM-CSF cytokine production in both Th0 and Th17conditions. The blood was pre-treated with apremilast and Tyk2 inhibitorBMS-986165 both alone and in combination using the TruCulture® TubeSystem. The IL-17A results located in FIG. 1 show the IL-17A% of controland all data is normalized to the Th17 DMSO control. Apremilastinhibited 28% of IL-17A cytokine expression under Th0 conditions and hadno effect in Th17 conditions. BMS-986165 had a similar effect under bothstimulation conditions and inhibited 10-25% of IL-17A expression at0.001-1 μM. When apremilast was combined with BMS-986165 under Th0conditions there was synergy seen with 1 μM BMS-986165 with a 65%reduction in IL-17A. Under Th17 conditions there was synergy with thecombination of 1 μM apremilast and 0.01 μM, 0.1 μM and 1 μM BMS-986165with inhibition of 24%, 44% and 85% of IL-17A respectively. FIG. 2 showsthe picograms per milliliter levels of IL-17A. Levels of IL-17Aincreased in the Th17 stimulation conditions by 387% compared to the Th0stimulation. In Th0 conditions apremilast reduced IL-17A levels from 138pg/mL to 93 pg/mL. BMS-986165, at 1 μM reduced IL-17A levels to 97pg/mL. The combination of apremilast with 1 μM BMS-986165 furtherreduced IL-17A levels to 24 pg/mL with the Th0 stimulation. Under Th17conditions the stimulation control measured 532 pg/mL and apremilast didnot inhibit IL-17A levels. BMS-986165 reduced IL-17A levels to 519 pg/mLat 0.01 μM, 428 pg/mL at 0.1 μM and 383 pg/mL at 1 μM. The combinationof 1 μM apremilast with BMS-986165 reduced IL-17A levels to 379 pg/mL at0.01 μM, 328 pg/mL at 0.1 μM and 68 pg/mL at 1 μM BMS-986165.

Example 2 Interleukin 17F Cytokine Production by Apremilast andBMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β,IL-6 and IL-23 (Th17) Stimulated Whole Blood

IL-17F cytokine expression data is in FIG. 3 and FIG. 4. Apremilastinhibited 69% of IL-17F production under Th0 conditions and 49% underTh17 conditions. BMS-986165 had a similar effect on IL-17F with both theTh0 and Th17 stimulation. There was 31% inhibition at the lowestconcentration of 0.001 μM and a dose response with 34% inhibition at0.01 μM, 70% inhibition at 0.1 μM and 95% inhibition of IL-17Fexpression at 1 μM (Th17 results). The combination of 1 μM apremilastwith BMS-986165 under Th0 conditions was partially additive withinhibition ranging from 60% at 0.001 to 95% at 1 μM. Under Th17conditions lower concentrations of BMS-986165 combined with apremilastshowed synergy. Apremilast combined with BMS-986165 at 0.001 μMinhibited 68% of IL-17F, 0.01 μM inhibited 70%, 0.1 μM inhibited 94% and1 μM inhibited 99% of IL-17F production under Th17 stimulationconditions. Levels of IL-17F in the Th0 stimulation control were 1085pg/mL and increased to 6524 pg/mL in the Th17 stimulation. Apremilastreduced IL-17F to 368 pg/mL in the Th0 stimulation and to 3643 pg/mL inthe Th17 stimulation. BMS-986165 significantly reduced IL-17F at 0.1 and1 μM in both stimulation conditions. There was significant inhibition ofIL-17F at all concentrations of BMS-986165 when combined with apremilastand under both stimulation conditions.

Example 3 Interleukin 22 Cytokine Production by Apremilast andBMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β,IL-6 and IL-23 (Th17) Stimulated Whole Blood

IL-22 cytokine expression data is in FIG. 5 and FIG. 6. Apremilastinhibited 85% of IL-22 cytokine expression under Th0 conditions and 41%under Th17 conditions. Under Th0 stimulation condition BMS-986165inhibited 16% of IL-22 at 0.01 μM, 86% at 0.1 μM and 91% at 1 μM. UnderTh17 stimulation conditions BMS-986165 had no effect on IL-22 cytokineexpression at 0.001 μM but inhibited 17% at 0.01 μM, 60% at 0.1 μM and70% at 1 μM. Under Th0 conditions the combination had similar effects toapremilast alone with ˜90% inhibition at all concentrations ofBMS-986165. The combination under Th17 conditions was synergist at 0.01μM with 60% inhibition and at 0.1 μM with 90% inhibition of IL-22cytokine expression. The Th0 stimulation control had 1085 pg/mL of IL-22and the Th17 control was 6524 pg/mL. Apremilast significantly loweredIL-22 levels to 368 pg/mL in the Th0 conditions and 3643 pg/mL in theTh17 conditions. BMS-986165 significantly lowered IL-22 cytokineexpression in both stimulation conditions at 0.1 μM and 1 μM. There wassignificant inhibition of IL-22 at all concentrations of BMS-986165 whencombined with apremilast and under both stimulation conditions.

Example 4 TNF-α Cytokine Production by Apremilast and BMS-986165 inanti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23(Th17) Stimulated Whole Blood

TNF-α cytokine expression data is located in FIG. 7 and FIG. 8.Apremilast inhibited 90% of TNF-α levels in Th0 conditions and 94% inTh17 conditions. In the Th0 stimulation BMS-986165 increased TNF-αexpression by 21% at 0.001 μM, 43% at 0.01 μM and 61% at 0.1 μM. At thehighest concentration of 1 μM BMS-986165 inhibited 66% of TNF-α cytokineexpression. There was a similar increase in TNF-α production seen withBMS-986165 under Th17 conditions with a 19% increase at 0.01 μM and a77% increase at 0.1 μM. There was also inhibition of TNF-α (68%) with 1μM BMS-986165 under Th17 stimulation conditions. The combination of 1 μMapremilast with BMS-986165 reduced levels of TNF-α by 80-95% (Th0) and93-96% (Th17), a similar effect to single agent apremilast. Bothstimulation conditions had a similar effect on levels of TNF-α with theTh0 stimulation control of 1380 pg/mL and the Th17 stimulation controlof 1436 pg/mL. Apremilast significantly inhibited TNF-α by reducinglevels to 148 pg/mL in Th0 conditions and 91 pg/mL in Th17 conditions.The increase in TNF-α levels by BMS-986165 was significant in Th17conditions at 0.1 μM. The inhibition of TNF-α levels with 1 μMBMS-986165 was significant under both stimulation conditions. Thecombination of apremilast with BMS-986165 significantly inhibited TNF-αlevels with all concentrations and in both stimulation conditions.

Example 5 Granulocyte-Macrophage Colony-Stimulating Factor CytokineProduction by Apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) oranti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) Stimulated Whole Blood

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) cytokineexpression results are in FIG. 9 and FIG. 10. GM-CSF cytokine expressionwas reduced 80% by apremilast under Th0 conditions and by 66% under Th17conditions. BMS-986165 increased GM-CSF cytokine expression under bothconditions. BMS-986165 increased GM-CSF by 19% at 0.001 μM, 36% at 0.01μM, 110% at 0.1 μM and 31% at 1 μM in the Th0 conditions. Whenapremilast (0.1 μM) was added to BMS-986165 there was inhibition 60-80%of GM-CSF cytokine expression. In the Th17 stimulation BMS-986165increased GM-CSF by 41% at 0.01 μM, 139% at 0.1 μM and 104% at 1 μM.When apremilast was added there was 40-73% inhibition of GM-CSF cytokineexpression. Total pg/mL of GM-CSF in the Th0 and Th17 stimulationcontrols were 409 and 637 respectively. Apremilast significantlyinhibited GM-CSF under both stimulation conditions. The increase ofGM-CSF by BMS-986165 was significant at 0.1 μM (both Th0 and Th17) and 1μM (Th17). The combination of apremilast and BMS-986165 significantlyreduced GM-CSF cytokine levels at all concentrations and under bothstimulation conditions.

Example 6 IL-23 Production in LPS Stimulated PBMCs with Apremilast andTyk2i (BMS-986165) Treatment

PBMCs from 9 healthy donors were analyzed for cytokine production in LPSstimulation condition (FIG. 11 to FIG. 17). Results in FIG. 11 and FIG.12 showed the level of IL-23. FIG. 11 showed that Apremilast decreasedIL-23 production in LPS stimulated PBMCs. IL-23 level from DMSO treatedLPS stimulated PBMCs was set as 100% (control), cytokine levels wereshown as normalized value in % compared to control. In contrast todecreasing IL-23 level by Apremilast, FIG. 12 showed that BMS-986165induces IL-23 level in LPS stimulated PBMCs. At the range of 0.2 μM-2μM, BMS-986165 induced a 20 fold increases of IL-23 compared to DMSOgroup. The combination of apremilast with BMS-986165 was able todecrease the induction of IL-23 by BMS-986165. With increased level ofapremilast, there is significant reduction of IL-23 level. Statisticalanalysis using ANOVA and Turkey's multiple comparisons were performed tocompare each treatment with BMS-986165 alone. There is significantreduction of IL-23 when combining BMS-986165 with low level ofapremilast, which is at the concentration of 0.037 μM (**** p<0.001).When combined with 1 μM apremilast, the induction of IL-23 was 90%inhibited, and almost reached a similar level as apremilast alone. Thus,the curve of combination treatment with 1 μM apremilast has nosignificant difference compared to apremilast treatment alone.

Example 7 IL-12p40 Production in LPS Stimulated PBMCs with Apremilastand Tyk2i (BMS-986165) Treatment

Results in FIG. 13 showed the normalized level of IL-12p40 compared toDMSO treated LPS stimulated PBMCs group. Apremilast decreased IL-12p40in a dose dependent manner, whereas BMS-986165 increased it. Thecombination of BMS-986165 with apremilast significantly decreased theinduction of IL-12p40 by BMS-986165. With 1 μM apremilast, the increasedIL-12p40 induced by BMS-986165 was 85% inhibited, and almost reached asimilar level as Apremilast alone. Statistical analysis using ANOVA andTurkey's multiple comparisons were performed to compare each treatmentwith BMS-986165 alone. **** p<0.001

Example 8 IL-12p70 Production in LPS Stimulated PBMCs with Apremilastand Tyk2i (BMS-986165) Treatment

Results in FIG. 14 showed the normalized level of IL-12p70 compared toDMSO treated LPS stimulated PBMCs group. Apremilast decreased IL-12p70in a dose dependent manner, whereas BMS-986165 increased it. Thecombination of BMS-986165 with apremilast significantly decreased theinduction of IL-12p70 by BMS-986165. In combination treatment, both 0.3μM and 1 μM significantly reduced IL-12p70 level induced by BMS-986165and have no significant difference compared to apremilast alone.Statistical analysis using ANOVA and Turkey's multiple comparisons wereperformed to compare each treatment with BMS-986165 alone. **** p<0.001

Example 9 TNF-α Production in LPS Stimulated PBMCs with Apremilast andTyk2i (BMS-986165) Treatment

Results in FIG. 15 showed the normalized level of TNF-α compared to DMSOtreated LPS stimulated PBMCs group. Apremilast decreased TNF-α level ina dose dependent manner, however, BMS-986165 induced 1.2-1.5 foldincrease of TNF-α. The combination of BMS-986165 and apremilastsignificantly decreased the level of TNF-α. Statistical analysis usingANOVA and Turkey's multiple comparisons were performed to compare eachtreatment with BMS-986165 alone. **** p<0.001

Example 10 IFN-γ Production in LPS Stimulated PBMCs with Apremilast andTyk2i (BMS-986165) Treatment

Results in FIG. 16 showed the normalized level of IFN-γ compared to DMSOtreated LPS stimulated PBMCs group. Both apremilast alone and BMS-986165alone decreased IFN-γ in a dose dependent manner. The combination ofBMS-986165 and apremilast has synergistic effect in reducing IFN-γ levelwhich significantly decreased IFN-γ level compared to single compoundtreatment. Statistical analysis using ANOVA and Turkey's multiplecomparisons were performed to compare each treatment with BMS-986165alone. **** p<0.001.

Example 11 MCP-1 Production in LPS Stimulated PBMCs with Apremilast andTyk2i (BMS-986165) Treatment

Results in FIG. 17 showed the normalized level of MCP-1 compared to DMSOtreated LPS stimulated PBMCs group. Both apremilast alone and BMS-986165alone decreased MCP-1 in a dose dependent manner. The combination ofBMS-986165 and Apremilast has synergistic effect in reducing MCP-1level. Statistical analysis using ANOVA and Turkey's multiplecomparisons were performed to compare each treatment with BMS-986165alone. **** p<0.001.

Data Summary

Table 5 below provides a summary of the cytokine effects of apremilastand BMS-986165 on stimulated whole blood in the Ex-Vivo TruCulture®Assay. Synergistic effects are shown in bold and complementary effectsare underlined.

Four healthy donors' whole blood was tested in the Tru-culture assay inTh0 (anti-CD3/anti-CD28) or Th17 (anti-CD3/anti-CD28+IL-1β, IL-6 andIL-23) conditions for 48 hours with the Tyk2 inhibitorBMS-986165+/−apremilast. BMS-986165 inhibited IL-17A, IL-17F, and IL-22cytokine expression under Th0 and Th17 conditions. When combined withapremilast these cytokines were further reduced with a synergisticeffect on IL-17A, IL-17F and IL-22 under Th17 conditions. BMS-986165increased TNF-α and GM-CSF production, while apremilast inhibitedproduction of these cytokines. When BMS-986165 was combined withapremilast there was a complementary effect on TNF-α and GM-CSF cytokineexpression, with apremilast correcting the defect of BMS-986165. Thesecombined effect provide means for treating diseases or disordersresponsive to the inhibition of PDE4 such as for the treatmentinflammatory diseases (e.g., psoriasis, psoriatic arthritis, andulcerative colitis).

TABLE 5 IL-17F IL-17A IL-22 TNF-α IL-23 GM-CSF IFN-γ IL-10 % of % of %of % of % of % of % of % of Stim. Treatment Control Control ControlControl Control Control Control Control Th0 1 μM 31.8 71.6 14.8 10.782.1 20.3 9.3 41.6 apremilast 0.01 μM 68.5 83.5 84.1 143.1 101.8 136.3100.2 101.5 BMS- 9896165 0.1 μM 28.3 73.0 13.4 160.7 89.9 210.5 80.933.8 BMS- 9896165 0.01 μM 33.8 84.0 11.2 13.5 79.3 27.4 12.2 42.0 BMS-9896165 + apr 0.1 μM 21.0 90.0 9.3 21.9 77.0 41.6 12.9 34.8 BMS-9896165 + apr Th17 1 μM 59.7 102.4 57.5 5.8 94.3 33.8 18.7 32.6apremilast 0.01 μM 73.6 97.7 83.3 118.5 93.8 141.1 114.2 78.4 BMS-9896165 0.1 μM 30.0 79.2 39.8 177.4 96.3 239.3 74.7 46.6 BMS- 98961650.01 μM 34.1 76.1 39.5 6.7 92.7 37.8 16.8 29.9 BMS- 9896165 + apr 0.1 μM11.5 66.1 9.2 8.2 84.2 60.8 8.4 45.4 BMS- 9896165 + apr CCL20 IL-13IL-10 IL-2 IL-21 IL-4 IL-5 IL-6 % of % of % of % of % of % of % of % ofStim. Treatment Control Control Control Control Control Control ControlControl Th0 1 μM 59.5 15.3 16.4 17.9 62.9 30.3 6.2 52.8 apremilast 0.01μM 82.7 146.9 113.5 120.1 107.6 122.8 153.1 149.3 BMS- 9896165 0.1 μM106.4 205.9 113.2 187.4 94.5 114.7 178.6 124.0 BMS- 9896165 0.01 μM 73.125.0 30.4 18.2 62.9 33.1 9.1 112.6 BMS- 9896165 + apr 0.1 μM 97.0 45.141.6 22.9 68.9 37.6 16.6 210.0 BMS- 9896165 + apr Th17 1 μM 220.3 22.198 14.4 76.2 36.7 4.8 95.3 apremilast 0.01 μM 121.7 158.1 94.2 128.591.5 126.5 144.3 96.8 BMS- 9896165 0.1 μM 157.8 287.5 89.0 250.3 86.3161.9 249.9 112.7 BMS- 9896165 0.01 μM 270.3 26.1 88.7 15.9 72.8 27.46.4 108.9 BMS- 9896165 + apr 0.1 μM 340.1 46.2 82.8 21.9 54.5 28.7 8.0101.1 BMS- 9896165 + apr

Table 6 below provides a summary of the cytokine effects of apremilastand BMS-986165 on LPS stimulated PBMCs. Arrows pointing up indicateinduction and arrows pointing down indicate decrease of the productionof cytokines. PBMCs from 9 healthy donors were tested in LPS stimulatedcondition with or without BMS-986165 or apremilast or the combination ofboth. BMS-986165 treatment alone induced IL-23, IL-12p40, IL-12p70 andTNF-α, whereas apremilast treatment alone decreased these cytokines.When BMS-986165 was combined with apremilast, these cytokines wereeither unchanged or reduced compared to DMSO control group. Theseresults indicate that apremilast could inhibit the induction of thesecytokines by BMS-986165. Both apremilast and BMS-986165 reduced IFN-γand MCP-1 production, and the combination of both further reduced thesetwo cytokines with a synergistic effect. BMS-986165 inhibits Th17lineage cytokines, which provide a means for treating diseases whereTh17 cytokines are implicated in the pathogenesis. However, theinduction of some proinflammatory cytokines, such as IL-23, IL-12 andTNF-α, by BMS-986165 could be a disadvantage in disease treatment. Thecombined effects of apremilast and BMS-986165 in which IL-23, IL-12 andTNF-α were decreased showed an advantage of combining these twocompounds in treating inflammatory diseases such as psoriasis, psoriaticarthritis, and ulcerative colitis.

TABLE 6 IL- IL- IL- TNF- MCP- GM- G- IL- IL- Viability 23 12p40 12p70 αIFNγ 1 CSF CSF 1β 1ra Apremilast — ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ — — BMS-986165 — ↑↑ ↑↑ ↑ ↓ ↓ ↑ ↑ — ↓ Combination — — ↓ — ↓ ↓↓ ↓↓ ↑ ↑ — ↓ IL- IL- IL- IL- IL-IFN IFS IL-2 4 IL-5 IL-6 10 13 IL-15 17 22 α2 Nβ Apremilast ↓ — — — ↑ —— — — — — BMS-986165 — — — — — ↑ — — — — — Combination ↓ — — — ↑ — — — —— — ↑ Induced — No change ↓ Reduced

1-49. (canceled)
 50. A pharmaceutical composition comprising atherapeutically effective amount ofN-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide,or a pharmaceutically acceptable thereof; and a therapeuticallyeffective amount of a Tyk2 inhibitor of the formula:

or a pharmaceutically acceptable salt thereof.
 51. (canceled)
 52. Thepharmaceutical composition of claim 50, wherein the composition isformulated for administration of from about 2 mg/day to about 14 mg/dayof the Tyk inhibitor.
 53. The pharmaceutical composition of claim 50,wherein the composition is formulated for administration of about 4mg/day, about 6 mg/day, or about 12 mg/day of the Tyk inhibitor.
 54. Thepharmaceutical composition of claim 50, wherein the composition isformulated for administration of from about 10 mg to about 60 mg per dayofN-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide,or the pharmaceutically acceptable salt thereof.
 55. (canceled) 56.(canceled)
 57. The pharmaceutical composition of claim 50, wherein thecomposition is formulated for administration of about 30 mg per day orabout 60 mg per day ofN-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide,or the pharmaceutically acceptable salt thereof.
 58. The pharmaceuticalcomposition of claim 50, wherein the composition is formulated foradministration of about 30 mg once daily ofN-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide,or the pharmaceutically acceptable salt thereof.
 59. The pharmaceuticalcomposition of claim 50, wherein the composition is formulated foradministration of about 30 mg twice daily ofN-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide,or the pharmaceutically acceptable salt thereof.
 60. The pharmaceuticalcomposition of claim 50, wherein the pharmaceutical composition is inthe form of a tablet or a capsule.
 61. The pharmaceutical composition ofclaim 50, wherein the pharmaceutical composition is formulated forextended release.
 62. The pharmaceutical composition of claim 50,wherein the pharmaceutical composition is formulated for immediaterelease.